1,2,3,4,6,7,12,12A-OCTAHYDRO-2-PHENYLPYRAZINO[2&#39;,1&#39;:6,1]PYRIDO[3,4-b]INDOLES AND INTERMEDIATES THEREFOR

ABSTRACT

New 1,2,3,4,6,7,12,12a-octahydro-2-phenylpyrazino(2&#39;&#39;,1&#39;&#39;: 6,1)pyrido(3,4-b)indoles having useful psychomotor stimulant properties are prepared by thermal cyclization of a 2-( Alpha halo-lower-alkanoy)-3-carbo-lower-alkoxy-1,2,3,4-tetrahydro-9Hpyrido(3,4 -b)indole with an aniline derivative, and alkali metal aluminum hydride reduction of the resulting 1,2,3,4,6,7,12,12aoctahydro-1,4-dioxo-2-phenylpyrazino -(2&#39;&#39;,1&#39;&#39;:6,1)pyrido(3,4b)indole.

United States Patent 1 Schulenberg PHENYLPYRAZINO [2 ",1 :6,1]PYRIDO[3,4-b] INDOLES AND INTERMEDIATES THEREFOR [75] Inventor: John W.Schulenberg, Delmas, NY.

[73] Assignee: Sterling Drug, Inc., New York, NY.

[22] Filed: March 11, 1971 [21] Appl. No.: 123,425

Related U.S. Application Data [62] Division of sef. No.331,750,1un'9,minim.

[451 Feb. 20, 1973 3,468,890 9/1969 Archer ..260/268 PC OTHERPUBLICATIONS Schulenberg et al., Chem. Abstr. Vol. 72, Col. 55396a(abstracting Jour. Med. Chem. Vol. 13, p. 145) Primary ExaminerDonald G.Dans Attorney-Elmer J. Lawson, B. Woodrow Wyatt, Thomas L. Johnson,Robert K. Bair, William G. Webb, Frederik W. Stonner and Theodore C.Miller [57] ABSTRACT New 1,2,3,4,6,7,i2, l2a-octahydro-2-phenylpyrazino[2,1:6,l ]pyrido[3,4-b]indoles havinguseful psychomotor stimulant properties are prepared by thermaleyclization of a 2-(a-halo-lower-alkanoy)-3- carbo-lower-alkoxy-1,2,3,4-tetrahydro-9H-pyrido[ 3 ,4- b]indole with an aniline derivative, andalkali metal aluminum hydride reduction of the resulting1,2,3,4,6,7,l2,12a-octahydr0-1,4-dioxo-2-phenylpyrazino-[2,1.:6,l]pyrid0[ 3,4-b]indole.

6 Claims, No Drawings 1,2,3,4,6,7,12,12A-CTAHYDRO-2-PHENYLPYRAZINO[2',1:6,1]PYRlDO[3 ,4-B] INDOLES AND INTERMEDIATESTHEREFOR v This application is a division of my prior, co-pending VIapplication Ser. No. 831,750, filed June 9, 1969, now i U.S. Pat. No.3,644,384, patented Feb.22, 1972.

ORGANIC COMPOUNDS AND THEIR Y PREPARATION k/mi N R 1 This inventionrelates to certain l,2,3,4,6,7,l2,l2a- 1O octahydro-2 -phenylpyrazino[2,1 ':6,1 ]pyrido[3 ,4- N b]indoles having the formula: I O 11 12 12a 0 lY "Q 15 a 2N- N R 1 1 6 I I I? I IV H o I where R,, R and R have themeanings given above, R where R is h are en or lowepalkyl; and R2 and R3represents lo wer-alkyhand X represents halogen. each are hydro gen rmethylenedioxy or ethylenedioxy The feachoh the loweralkyl a v yattached to adjacent carbon atoms or from one to three9H'pynd[3*4'blmdole'zl'carboxylhtes of formual H members of the groupconsisting of halogen (including wlth the a'halo'loweralkahoyl hhhdesProduce h fluorine, chlorine, bromine, and iodine), lower-alkyl,compouhds of formula m Fh out m an Prgahlc lowepalkoxy,lowepalkylmer'capito, amino) solvent mert under the conditions of thereactlon, for kylamino,tri fluoromethylor hydroxy ei campl e chloroform,methylene dichlorlde, ethylene The compounds of formula I are f l aspsychomo dichloride, benzene, toluene, dioxape, and the like, and torstimulants as more fully described hereinafter. at temperahre of fromaround 10 to about 100 As used herein the term lower-alkyl means satu-The macho of the y rated, monovalent hydrocarbon radicals, including Yl' 'PY QQ hf l straight or branched chain radicals of from one to sixcarboxylates of formula Ill with an aniline derivative of carbon atomsas illustrated by, but not limited to, formula VI topmduce the fhpoffol'mula Y 15 methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl, amylgenerally carried out by heatmg the reactants in a high h l d h 1ikbo1l1ng polar solvent, for example 2-ethoxyethanol, The compounds offormula I are prepared by reacp py g y ethylene g y and the like- The tif a lowe -alkyl 13 3 4-t t h d 9fiid [3 4- reaction is preferablycarried out at the boiling point of b]indole-3-carboxylate of formula IIwith an a-halothe Solvent used lower-alkanoyl halide; heating theresulting lower-alkyl 40 The reduction of the y2-(a-halo-lower-alkanoyl)-l ,2,3 ,4-tetrahydro-9l-l- -P Y Py l 'J' lPy 11 pyrido[3,4-b]indole-3-carboxylate of formula III ith doles of formulaIV to the final products of formula 1 is an aniline derivative,generally carried out at a temperature in the range from about 20 toabout 80C. in an organic solvent inert under the conditions of thereaction, for example diethyl ether or tetrahydrofuran. It is preferredto carry I out the reaction in tetrahydrofuran at the boiling pointthereof. and reduction, with an alkali metal aluminum hydride, Thelower-alkyl 1,2,3,4-tetrahydro-9H-pyrido[3,4- of the resultingl,2,3,4,6,7,l2,12a-octahydro-l,4- 5O bl-indole-3-carboxylates of formulaII are generally dioxo-Z-phenylpyrazino-[2,l ':6,l ]pyrido[3,4-b]inknowncompounds and are prepared from known trypdole of formula IV. Thereactions are represented by tophanes having formula V: 4 i

the equations:

R N112 A -o o o R A; R3 X HCOX I I]:

n by reaction of the latter with in i the presence of a basic catalyst,and esterification of the resulting l,2,3,4- m I /L/tetrahydro-9H-pyrido[3,4-b]indole-3-carboxylic acid N-COCHX with alower-alkanol in the presence of an acid catalyst.

\N Due to the presence of two basic amino nitrogen 11 atoms, thecompounds of formula 1 form acid-addition 111 salts. The compounds offormula 1, in free base form,

are converted to the acid-addition salt form by interaction of the basewith an acid. In like manner, the free bases can be regenerated from theacid-addition salt form in the conventional manner, that is by treatingthe salts with strong aqueous bases, for example alkali metalhydroxides, alkali metal carbonates, and alkali metal bicarbonates. Thebases thus regenerated can then be interacted with the same or adifferent acid to give back the same or different acid-addition salt.Thus the novel bases and all of their acid-addition salts are readilyinterconvertible.

The salts are useful as characterizing or identifyingderivatives of thefree bases or in isolation or purification procedures. Suchcharacterizing or purification acid-addition salt derivatives, like allof the acid-addition salts, can if desired, be used to regenerate thefree bases by reaction of the salts with aqueous base, or alternativelythe acid-addition salt can be converted to a different characterizing oridentifying salt by, for example, ion-exchange procedures. Thereforalthough toxicity, insolubility, or lack of crystalline character maymake some particular salt species unsuitable or less desirable for useas such in a given identification or purification procedure, such saltscan be converted to the free base by decomposition of the acid-additionsalt with aqueous base as explained, or alternatively, the acid-additionsalt can be converted to a more suitable salt species by doubledecomposition reactions involving the anion, for example, byion-exchange procedures.

It will be appreciated from the foregoing that all of the acid-additionsalts of the new bases are useful and valuable compounds regardless ofconsiderations of toxicity, solubility, physical form, and the like.

The novel features of the compounds of the invention, then, reside inthe concept of the bases and the cationic forms of the new compounds offormula I and not in any particular acid moiety or anion associated withthe salt forms of the compounds; rather, the acid moieties or anionswhich can be associated in the salt forms are in themselves neithernovel nor critical and therefore can be any anion or acid-like substancecapable of salt formation with bases. In fact, in aqueous solutions, thebase form or water-soluble acid-addition salt form of the compounds ofthe invention both possess a common protonated cationor ammonium ion.

Thus appropriate acid-addition salts are those derived from such diverseacids as formic acid, acetic acid, isobutyric acid,alpha-mercaptopropionic acid, malic acid, fumaric acid, succinic acid,succinamic acid, tartaric acid, citric acid, lactic acid, benzoic acid,4-methoxybenzoic acid, phthalic acid, anthranilic acid, 1 -naphthalenecarboxylic acid, cinn amic acid, cyclohexanecarboxylic acid,mandelic acid, tropic acid, crotonic acid, acetylene dicarboxylic acid,sorbic acid, Z-furancarboxylic acid, cholic acid, pyrenecarboxylic acid,Z-pyridinecarboxylic acid, 3-indoleacetic acid, quinic acid, sulfamicacid, methanesulfonic acid, isethionic acid, benzenesulfonic acid,p-toluenesulfonic acid, benzenesulfinic acid, butylarsonic acid,diethylphosphinic acid, p-aminophenylarsinic acid, phenyl stibnic acid,phenylphosphinous acid, methylphosphinic acid, phenylphosphinic acid,hydrofluoric acid, hydrochloric acid, hydrobromic acid, hydriodic acid,perchloric acid, nitric acid, sulfuric acid, phosphoric acid,hydrocyanic acid, phosphotungstic acid, molybdic acid, phosphomolybdicacid, pyrophosphoric acid, arsenic acid, picric acid, picrolonic acid,barbituric acid, or boron trifluoride. Example The acid-addition saltsare prepared either by dissolving the free base in an aqueous solutioncontaining the appropriate acid and isolating the salt by evaporatingthe solution, or by reacting the free base and acid in an organicsolvent, in which case the salt separates directly or can be obtained byconcentra-tion of the solution.

Pharmacological evaluation of the compounds of formula I according tostandard pharmacological test procedures has demonstrated that theypossess psychomotor stimulant activity, thus indicating their use tocombat depressed states, e.g. as psychic energizes. Similarly,pharmacological evaluation of the compounds of formula IV according tostandard pharmacological test procedures has demonstrated that theypossess psychomotor depressant activity, thus indicating theirusefulness as C.N.S. depressants, for example, as tranquilizers.

The psychomotor depressant and stimulant activities of the compounds offormulas I and IV were determined in standard activity cages using themethod of Dews, Brit. J. Pharmacol. 8, 46 (1953) in which mice,medicated with the test compound, are placed in wire mesh cages equippedwith a photoelectric cell so adjusted that a mouse breaking the beamactivates a magnetic digital counter. Thus the number of times the lightbeam is broken over a period of time is an indication of the motoractivity of the animals, and a reduction or an increase in the number ofcounts in the medicated mice over control groups, run simultaneously, istaken as evidence of psychomotor depressant or psychomotor stimulantactivities, respectively. The dose at which such reduction or increasein motor activity is observed is recorded as the active dose.Alternatively, the ED the Effective Dose in 50 percent of the animals,is determined from a dose-response curve.

Instead of determining the motor activity of the test animals using adigital counter activated by a photoelectric cell, there can also beused a counting apparatus such as described by Bonta et al., Arch. int.pharmocodyn. I29, 38l-394 (1960) in which vertically movable leafsprings affixed to the activity cages activate a direct current amperehour meter which serves as a counter of the recorded activity. Moreover,v

as these authors show, compounds which depress motor activity of mice insuch activity cages are indicated to possess tran-quilizer activity. Themethod is also shown to be applicable in determining the activity oftremor inducing substances, i.e. C.N.S. stimulants, which are usefulpharmacological tools for investigating anti-Parkinson drugs.

The compounds of formulas I and IV of the invention, when administeredorally to mice in the abovedescribed psychomotor activity test, werefound to be active in the dose range of from 8 to 300 mg./kg. of bodyweight.

The compounds can be prepared for use by dissolving or suspending themin aqueous alcohol, glycol or oil solution, or oil-in-water emulsions inthe same manner as conventional medicinal substances are prepared.Alternatively, they can be incorporated in unit dosage form as tabletsor capsules for oral administration either alone or in combination withsuitable adjuvants such as calcium carbonate, starch, lactose, talc,magnesium stearate, gum acacia, and the like. The compounds areadministered to any suitable mammalian host in a dose range of 2-100mg./kg.

The chemical structures of the compounds of the invention areestablished by their mode of synthesis and are corroborated by infraredand ultraviolet spectra and by the correspondence between calculatedvalues for the elements and values found by chemical analysis.

The following examples will further illustrate specific embodiments ofthe invention. The melting points are uncorrected.

EXAMPLE 1 Ethyl 2-/a-ch1oroacetyl)-l ,2,3 ,4-tetrahydro-91-1-pyrido[3,4-b]-indole-3-carboxylate [111: R is H; R is H; R is c n To astirred solution of 10.01 g. (0.04 mole) of ethyll,2,3,4-tetrahydro-9H-pyrido[3,4-b]indo1e-3-carboxylate in 200 ml. ofchloroform was added with stirring over a period of forty minutes, asolution of 7.5 ml. (0.10 mole) of a chloroacetyl chloride in ml. ofchloroform. When addition was complete, the mixture was stirred for anadditional 10 minutes at room temperature, and then stirred under refluxfor 6 hours. The mixture was then diluted with ml. of isopropanol,evaporated to dryness, and the greenish tan solid residue wasrecrystallized from a benzene/heptane mixture giving 11 g. of ethyl2-(a-chloroacetyl)-1,2,3,4,-tetrahydro-9H-pyrido[3,4-b]-indole-3-carboxylate, m.p. 1502. -l52,8C.(corr.). Anal, Calcd. c n cm o Cl, 11.06; N, 8.74.

Found: Cl, 11.37; N, 8.93.

for

EXAMPLE 2 Ethyl tetrahydro-9H-pyrido -[3,4-b]indole -3-carboxylate [111:R is H; R is 7-CH O; R is C 11 is prepared by reaction oflX-ChiOl'OfiCBtYl chloride with ethyl 7- methoxy-l,2,3,4-tetrahydro-9H-pyrido[ 3 ,4-b]indole- 3-carboxylate (prepared byreaction of formaldehyde with 6-methoxytryptophane and esterification ofthe resulting carboxylic acid with. ethanol) using the proceduredescribed above in Example 1.

EXAMPLE 3 Ethyl 2-(a-chloroacetyl)-6,7-dimethoxy-l ,2,3,4- tetrahydro-9H-pyrido[3,4-b]indole-3-carboxylate [111: R is H; R is 6,7-(CH O) R is Cl-1 is prepared by reaction of a-chloroacetyl chloride with ethyl 6,7-dimethoxy-l,2,3,4-tetrahydro-9H-pyrido -[3,4-b]indole-3-carboxylate(prepared by reaction of formaldehyde with 5,6-dimethoxytryptophane andesterification of the resulting carboxylic acid with ethanol) using theprocedure described above in Example 1.

EXAMPLE 4 Ethyl 2-(a-chloroacetyl)-6-ethoxy-l,2,3,4-tetrahydro-9H-pyrido- [3,4-b]indole-3-carboxylate [111: R is 1-1;R is 6-C H O; R isC 11,] is prepared by reaction of achloroacetyl chloride with ethyl6-ethoxy-l,2,3,4,- tetrahydro-9H-pyrido[3,4-b]indole-3-carboxylate(prepared by reaction of formaldehyde with S-ethoxy tryptophane andesterification of the resulting carbox-2-(a-chloroacetyl)-7-methoxy-1,2,3,4-

ylic acid with ethanol) using the procedure described above in Example1.

EXAMPLE 5 Ethyl 2-(a-chloroacetyl)-7-methyl-1,2,3,4-tetrahydro-9H-pyrido-{3,4-b]indole-3-carboxylate [111: R is 1-1; R is 7-C1-1 R is C11 is prepared by reaction of achloroacetyl chloride with ethyl7-methyl-l,2,3,4- tetrahydro-9 l-l-pyrido[ 3 ,4-b indole-3-c arboxylate(prepared by reaction of formaldehyde with 6methyltryptophane andesterification of the resulting carboxylic acid with ethanol) using theprocedure described above Example 1.

EXAMPLE 6 Ethyl 2(a-chloroacetyl)-5,7-dimethyl-l ,2,3 ,4-tetrahydro-9H-pyrido[3,4-b]indole-3-carboxylate [111: R is H; R is5,7-(CH R is C 11 is prepared by reaction of a-chloroacetyl chloridewith ethyl 5,7- dimethyl-l ,2,3,4-tetrahydro-9H-pyrido[3,4-blindole-3-carboxylate (prepared by reaction of formaldehyde with4,6dimethyltryptophane and esterification of the resulting carboxylicacid with ethanol) using the procedure described above Example 1.

EXAMPLE 7 Ethyl Z-(a-chloroacetyl)-6-benzyloxy-l ,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole-3-carboxylate [111: R is H; R is 6-C HCH O; R is C 11 is prepared by reaction of a-chloroacetyl chloride withethyl 6- benzyloxy-l ,2,3,4-tetrahydro-9H-pyrido-[3,4-b1indole-3-carboxylate (prepared by reaction of formal-, dehyde withS-benzyloxy tryptophane and esterification of the resulting carboxylicacid with ethanal) using the procedure described above in Example 1.

EXAMPLE 8 Ethyl 2-(a-chloropropionyl)-7-chloro-1 ,2,3 ,4-tetrahydro-9H-pyrido[3,4-b]indole-3-carboxylate [111: R is CH R is 7-Cl;R is C l-1 is prepared by reaction of a-chloropropionyl chloride withethyl 7-chlorol ,2,3 ,4-tetrahydro-9H-pyrido[ 3,4-b]indole-3-carboxylate (prepared by reaction of formaldehyde with 6-chlorotryptophane and esterification of the resulting carboxylic acidwith ethanol) using the procedure described above in Example 1.

EXAMPLE 9 Ethyl Z-(a-chloroacetyl)-6-bromo-1,2,3,4-tetrahydro-91-l-pyrido-[3,4-b]indole-3-carboxylate [111: R is H; R is 6Br; R is C His prepared by reaction of achloroacetyl chloride with ethyl6-bromo-1,2,3,4- tetrahydro-9H-pyrido[3,4-b]indole-3-carboxylate(prepared by reaction of formaldehyde with 5- bromotryptophaneesterification of the resulting carboxylic acid with ethanol) using theprocedure described above in Example 1.

EXAMPLE 10 Ethyl Z-(a-chloroacetyl)-6-fluoro-l ,2,3,4-tetrahydro-9H-pyrido-[3,4-blindole-3-carboxylate [111: R is H: R is 6-F; R is C 11is prepared by reaction of achloroacetyl chloride with ethyl6-fluoro-l,2,3,4- tetrahydro-9H-pyrido[3,4-b]indole-3-carboxylate(prepared by reaction of formaldehyde with 5- fluorotryptophane andesterification of the resulting carboxylic acid with ethanol) using theprocedure described above in Example 1.

EXAMPLE 1 l Ethyl 2-(a-chloroacetyl)-6-ido-1,2,3 ,4-tetrahydro-91-1-pyrido-[3,4-b]indole-3-carboxylate [111: R is 1-1; R is 6-1; R is C 11is prepared by reaction of achloroacetyl chloride with ethyl6-iodo-l,2,3,4- tetrahydro-QH-pyrido 3 ,4-b indole-3 -carboxylate(prepared by reaction of formaldehyde with 5- iodotryptophaneesterification of the resulting carboxylic acid with ethanol) using theprocedure described above in Example 1.

EXAMPLE 12 Ethyl 2(a-chlorobutyryl)-7 -hydroxyl ,2,3 ,4-tetrahydro-9H-pyrido-[3,4-b]indole-3-carboxylate [111: R is C 11 R is7-110; R is C H is prepared by reaction of a-chlorobutyryl chloride withethyl 7-hydroxyl ,2,3 ,4-tetrahydro-91-1-pyrido[ 3,4-b]indole-3-carboxylate (prepared by reaction of formaldehyde with 6-hydroxy-tryptophane and esterification of the resulting carboxylic acidwith ethanol) using the procedure described above in Example 1.

EXAMPLE 13 by reaction of -trifluoromethylindole with formal dehyde anddimethylamine, reacting the resulting gramine derivative with ethyla-acetylaminomalonate in the presence of two equivalents of dimethylsulfate and one equivalent of sodium ethoxide, and refluxing theresulting malonic ester derivative in dilute sulfuric acid to effectsimultaneous hydrolysis of the ester and the acetylamino groups as wellas decarboxylation of one of the carboxyl functions, all as known in theart.

EXAMPLE 14 Ethyl 2-(a-chloroacetyl )-6-methylmercapto-l ,2,3 ,4-tetrahydro-91-1-pyrido[3,4-blindole-Ii-carboxylate [111: R, is H; R is6-CH S; R is C 11 is prepared by reaction of a-chloroacetyl chloridewith ethyl 6-methy1mercapto-1,2,3 ,4-tetrahydro-9H-pyrido[3,4-bl-indole-3-carboxylate (prepared by reaction of formaldehyde with.5-methylmercaptotryptophane esterification of the resulting carboxylicacid with ethanol) using the procedure described above in Example 1.

The 5-methylmereaptotryptophane in turn is prepared by reaction ofS-methylmercaptoindole with formaldehyde and dimethylamine in thepresence of two equivalents of dimethyl sulfate and one equivalent ofsodium ethoxide, reacting the resulting gramine derivative with ethyla-acetylaminomalonate, and refluxing the resulting malonic esterderivative in dilute sulfuric acid to effect simultaneous hydrolysis ofthe ester and acetylamino groups as well as decarboxylation of one ofthe carboxyl functions, all as known in the art.

EXAMPLE 15 Ethyl 2-(a-chloroacetyl )-6,7-methylenedioxy-l ,2,3 ,4-tetrahydro-9H-pyridol3,4-b]indole-3-carboxylate [111:

R is 1-1; R is 6,7-OCH O; R is C l-1 is prepared by reaction ofa-chloroacetyl chloride with ethyl 6,7- methylenedioxyl ,2,3,4-tetrahydro-9H-pyrido[3,4- blindole-B-carboxylate (prepared byreacting formaldehyde with 5,6-methylenedioxytryptophane andesterification of the resulting carboxylic acid with ethanol) using theprocedure described above in Example l. The5,6-methylenedioxytryptophane prepared by reaction of 5,-methylenedioxyindole with formaldehyde and dimethylamine in thepresence of two equivalents of dimethyl sulfate and one equivalent ofsodium ethoxide, reacting the resulting gramine derivative with ethyla-acetylaminomalonate, and refluxing the resulting malonic esterderivative in dilute sulfuric acid to effect simultaneous hydrolysis ofthe ester and acetylamino groups as well as decarboxylation of one ofthe carboxyl functions, all as known in the art.

EXAMPLE l6 Ethyl 2-(a-chloroacetyl)-7-amino-1,2,3 ,4-tetrahydro-91-1-pyrido-[3,4-b1indole-3-carboxylate [111: R is 1-1; R is 7-N1-1 R isC 11 is prepared by reaction of achloroacetyl chloride with ethyl7-amino-l,2,3,4- tetrahydro-9H-py rido 3 ,4-b indole-Q-carboxylate(prepared by reaction of formaldehyde with 6- aminotryptophane andesterification of the resulting carboxylic acid with ethanol) using theprocedure described above in Example 1.

EXAMPLE 17 Ethyl Z-(a-chloroacetyl)-6-dirnethyl'amino-1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole-3-carboxylate [111:

R is H; R; is 6-(CI-1 N; R is C 11 is prepared by reaction ofa-chloroacetyl chloride with ethyl 6- dimethylamino-1,2,3,4-tetrahydro-9H-pyrido[ 3 ,4-b] indole-3-carboxylate (prepared byreaction of formaldehyde with 5-dimethylaminotryptophane andesterification of the resulting carboxylic acid with ethanol) using theprocedure described above in Example 1.

EXAMPLE 18 Ethyl Z-(a-chloroacetyl)-6-methyl-8-chloro-1,2,3,4-

tetrahydro-9H-pyrido[3,4-b]indole-3-carboxylate [111:

R is H; R, is 6-(IH -8-Cl; R is C l-1 is prepared by reaction ofa-chloroacetyl chloride with ethyl 6- methyl-8-chloro-1,2 ,3,4-tetrahydro-9H-pyrido[3 ,4-

blindole-3-carboxylate (prepared by reaction of formaldehyde with5-methyl-7-chlorotryptophane and esterification of the resultingcarboxylic acid with ethanol) using the procedure described above inExample 1.

in turn is Ethyl 2-( a-chloroacetyl)-6,7-ethylenedioxyl ,2,3 ,4-tetrahydro-9H-pyrido[3,4-b]indole-3-carboxylate [111: R is H; R is6,7-OCH CH O; R is C H is prepared by reaction of oz-ehloroacetylchloride with ethyl 6,7- ethylenedioxyl ,2,3,4-tetrahydro-9H-pyrido[ 3,4-b indole-3-carboxylate (prepared by reaction of formaldehyde with5,6-ethylenedioxytryptophane and esterification of the resultingcarboxylic acid with ethanol) using the procedure described above inExample 1.

The 5,6-ethylenedioxytryptophane in turn is prepared by reaction of 5,6-methylenedioxyindole with formaldehyde and dimethylamine, reactingthe resulting grarnine derivative with ethyl oracetylaminomalonate inthe presence of two equivalents of dimethyl sulfate and one equivalentof sodium ethoxide, and refluxing the resulting malonic ester derivativein dilute sulfuric acid to effect simultaneous hydrolysis of the esterand acetylamino groups as well as decarboxylation of one of the carboxylfunctions, all as known in the art.

EXAMPLE 1,2,3 ,4,6,7 ,12,12a-Octahydro-l ,4-dioxo-2-phenylpyrazino-[Z,1:6,1]pyrido[3,4-b]indole [1V: R R and R are H].

A mixture of 6.42 g. (0.02 mole) of ethyl 2-(achloroacetyl)-1,2,3,4-tetrahydro-9H-pyrido[ 3,4-b]indole-3-carboxylate and 2.35 ml. (0.04mole) of aniline in 100 ml. of 2-ethoxyethanol was heated and stirredunder reflux for eighteen hours, and the reaction mixture was thenconcentrated to a volume of 40 ml. in vacuo. The residual brownsuspension was diluted with 400 ml. of ethyl acetate, the mixture washedfour times with water, then three times with saturated sodium chloridesolution, dried briefly over magnesium sulfate, filtered, and taken todryness in vacuo. The residue was once again dissolved in 250 ml. of hotethyl acetate, and the mixture was chilled and filtered to remove asmall amount of tan insoluble material. The filtrate was chromatographedon a column of 350 g. of silica gel, and the column eluted with ethylacetate, 500 ml. fractions of eluate being collected. The first oneliter of eluate afforded a small amount of a brown glass and some solidwhich was discarded, and the next liter afforded a total of about threegrams of a tan solid. The latter was recrystallized from ethyl acetateto give 2.12 g. of 1,2,3,4,6,7,12,12a-octahydro-1,4-dioxo-2-phenylpyrazino[2',1':6,1]pyrido[3,4-b]indole,m.p. 252.22 53.4C. (corr.).

Anal. Calcd. for C H, N O C, 72.49; H, 5.17; N,

12.69. Found: C, 72.19; H, 5.35; N, 12.35.

EXAMPLE 21 1,2,3 ,4,6,7,12,12a-Octahydro-1,4-dioxo-9-methoxy-2(4-bromophenyl)pyrazino[2',1':6,1]pyrido[-b]indole [1V: R is H; R is4-Br; R is 9-CH O] is prepared by reaction of ethylZ-(a-chloroacetyl)-7-methoxy 1,2,3,4-tetrahydro-9H-pyrido-[3,4-b]indole-3-carboxylate with 4-bromonanilinein 2-ethoxyethano1 using the procedure described above in Example 20.

EXAMPLE 22 EXAMPLE 23 1,2,3 ,4,6,7,l 2,1 2a-Octahydro-1 ,4-dioxo-10-ethoxy-2- dole [1V: R is H; R is 4-Cl; R is l0-C H O] is prepared byreaction of ethyl 2-(a-chloroacetyl)-6- eth0xy-1,2,3,4-tetrahydro-91-l-pyrido[ 3 ,4-b]-indole-2- carboxylate with4-chloroaniline in 2-ethoxyethano1 using the procedure described abovein Example 20.

EXAMPLE 24 l,2,3,4,6,7,12,l2a-Octahydro-l,4-dioxo-9-methyl-2-(3-methylmercepatophenyl)pyrazino[2,l ':6,1 ]pyrido[3,4-b]ind0le [IV: R,is H; R is 3-CH S; R is 9- CH is prepared by reaction of ethyl2-(achloroacetyl)-7-methyl-l ,2,3,4-tetrahydro-9H-pyrido-[3,4-b]indole-3carboxylic with 3-methylmercaptoaniline in2-ethoxyethanol using the procedure described in Example 20.

EXAMPLE 25 l ,2,3,4,6,7,l2,12a-Octahydro-1,4-dioxo-9,1ldimethyl-2-[4-(N,N-dimethylamino)phenyl]pyrazino{2',l:6,1]pyrido[3,4-b]indole [IV: R, is H; R is 4-(CH N; R is 9,1l-(CH is prepared by reaction of ethyl2-(a-chloroacetyl)-5,7-dimethyl-1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole-3-carboxylate with4-(N,N-dimethylamino)aniline in Z-ethoxyethanol using the proceduredescribed above in Example 20.

EXAMPLE 26 1 ,2,3,4,6,7,12,1Za-Octahydro-l ,4-dioxo-10-benzyloxy-2-(3-trifluoromethylphenyl)pyrazino [2',1 :6,l] pyrido [3 ,4-b] indole[1V: R1 is H; R is 3-CF5; R is1O-C H5CH2O] is prepared by reaction ofethyl 2-(achloroacetyl)-6-benzyloxy 1,2,3 ,4-tetrahydro-9H- pyrido[ 3,4-b indole-3 -carboxylate with 3 trifluoromethylaniline in2-ethoxyethanol using the procedure described above in Example 20.

EXAMPLE 27 1 ,2,3,4,6,7,l2,12a-Octahydro-l ,4-dioxo-9chloro-3-methyl-2-(2,4,6-trimethylphenyl)pyrazino[2,1 ':6,1] pyrido[3,4-b]indole[1V: R is Ch R is 2,4,6-(CH R is 9-Cl] is prepared by reaction of ethyl2-(achloropropionyl)-7-chloro-1,2 ,3 ,4-tetrahydro-9H-pyrido[3,4-b]indole-3-carboxylate with 2,4,6- trimethylaniline in2-ethoxyethanol using the procedure described above in Example 20.

EXAMPLE 28 l,2,3,4,6,7,l2,12a-Octahydro-1,4-dioxo-l0-bromo-2-(3,4-methylenedioxyphenyl)pyrazino[2 ',1 :6,1]pyrido[cz3,4-b]indole [lV:R is H; R is 3, OCH O; R is IO-Br] is prepared by reaction of ethyl 2-(a-chloroacetyl)-6-bromo-l ,2,3 ,4-tetrahydro-9H- pyrido-[ 3,4-b]indole-3-carboxylate with 3 ,4- methylenedioxyaniline in2-ethoxyethanol using the procedure described above in Example 20.

Example 29 l ,2,3 ,4 ,6 ,7 ,12,12a-Octahydro-l,4-dioxo-10-flu0ro-2-(3,4-ethylenedioxyphenyl)pyrazino[2',l ':6,l ]pyrido[ 3, 4-b]indole [IV:R1 is H; R is 3,4-OCH2 CHQO; R3 is IO-F] is prepared by reaction ofethyl 2(achloroacetyl)-6-fluoro-1,2,3 ,4-tetrahydro-9H-pyrido-[3,4-b]indole-3-carboxylate with 3,4-ethylenedioxyaniline in2-ethoxyethanol using the procedure described in Example 20.

EXAMPLE 30 l ,2 ,3 ,4,6,7 l 2,1 Za-Octahydrol ,4-dioxo-l -iodo-2-(3,4-diethoxyphenyl)pyrazino[2',l:6,1]pyrido[- b]indole [lV: R, is H; R,is 3,4-(C H O),; R is 10-1] is prepared by reaction of ethyl2(a-chloroacetyl)-6- iodo-l ,2 ,3 ,4-tetrahydro-9H-pyrido-[ 3,4-b]indole-3 carboxylate with 3 ,4-diethoxyaniline in 2-ethoxyethanolusing the procedure described above in Examprocedure described above inExample 20.

EXAMPLE 32 1,2,3 ,4,6,7 ,1 2,12a-Octahydro-l ,4-dioxo-9-trifluoromethyl-2-(3-hydr0xyphenyl)pyrazino[2' ,l :6,l]indole [IV: R, isH; R, is S-HO; R is 9-CF is prepared by reaction of ethyl2-(ot-chloroacetyl)-7- trifluoromethyl-1,2 ,3 ,4-tetrahydro-9H-pyrido 3,4- b]indole-3-carboxylate with 3-hydroxyaniline in 2- ethoxyethanolusing the procedure described above in. Example 20.

EXAMPLE 33 1,2,3 ,4,6,7 ,l2,12a-Octahydro-l,4-dioxo-lO-methylmercapto-2-phenylpyrazino[2' ,1 :6,l ]pyrido[ 3,4-b]indole [IV: R, is H; R, is H; R, is 10-CH;,S] is prepared byreaction of ethyl Z-(a-chloroacetyl)-6-methylmercapto-l ,2,3,4-tetrahydro-9H-pyrido-[ 3 ,4-b1indole-3-carboxylate with aniline inZ-ethoxyethanol using the procedure described above in Example 20.

EXAMPLE 34 1,2,3 ,4,6,7,l 2,12a-Octahydrol ,4-dioxo-9,l0-methylenedioxy-Z-phenylpyrazino[2',1 :6,l ]pyrido[3,4]indole [1V2 R, isH; R is H; R is 9,10- OCH O] is prepared by reaction of ethyl2-(achloroacetyl )-6,7-methylenedioxyl ,2,3 ,4 ,-tetrahydro-9H-pyrido[3,4-b]indole-S-carboxylate with aniline in Z-ethoxyethanolusing the procedure described above in Example 20.

EXAMPLE 35 1,2,3 ,4 ,6 ,7 1 2, 1 2a-Octahydro- ,4-dioxo-9-amino-2-phenylpyrazino-[2',l ':6,l]pyrido[3,4-b]indole [IV: R, is H; R is H; Ris 9-NH is prepared by reaction of ethyl2-(a-chloroacetyl)-7-amino-1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole-3-carboxylate with aniline in 2-ethoxyethanolusing the procedure described above in Example 20.

EXAMPLE 36 1 ,2,3,4,6,7,1 2,12a-0ctahydro-1,4-c1ioxo-l0-dimethylamino-2-phenylpyrazino[2',l ':6,1 ]pyrido[3,4 -b]indole [IV: R,is H; R, is H; R, is l0-(CH ),N] is prepared by reaction of ethyl2-(a-chloroacetyl)-6- dimethylamino-l ,2,3 ,4-tetrahydro-9H-pyrido-[3,4- b]indole-3 carboxylate with aniline in 2-ethoxyethanol using theprocedure described above in Example 20.

EXAMPLE 37 1,2,3 ,4,6,7,l 2,12a-Octahydro l ,4-dioxo-10-methyl-8-chloro-2-phenylpyrazino[2 ,1":6,l ]pyrido[-b]indole [IV; R, is H; R isH; R, is l0-Cl-l -8-Cl] is prepared by reaction of ethyl2-(a-chloroacetyl)-6- methyl-8-chloro-1,2,3 ,4-tetrahydro-9H-pyrido 3,4-b] indole-3-carboxylate with aniline in Z-ethoxyethanol using theprocedure described above in Example 20.

EXAMPLE 38 l ,2,3,4,6,7,12,12a-Octahydro-l,4-dioxo-9,10-ethylenedioxy-2-phenylpyrazino[2',l ':6,l ]pyrido[3,4- b]indole [IV: R,is H; R is H; R is 9,l0-OCH CH O] is prepared by reaction of ethyl2-(a-chloroacetyl)-6,7- ethylenedioxy-1,2,3 ,4-tetrahydro-9H-pyrido[ 3,4-b]indole-3-carboxylate with aniline in Z-ethoxyethano] using theprocedure described above in Example 20.

EXAMPLE 39 1,2,3 ,4,6,7,12, l 2a-Octahydro-2-phenylpyrazino[ 2',1:6,l]pyrido-[3,4-b]indole [1: R,, R and R are H]. A mixture of 5.70 g.(0.017 mole) 1 ,2,3,4,6,7,12,12a-octahydro-l,4-di0xo-2-phenylpyrazino{2',1:6,1]pyrid0[{3,4-b]-indole and 3.26 g.(0.09 mole) of lithium aluminum hydride in 500 ml. of tetrahydrofuranwas heated and stirred under reflux for 48 hours, then cooled, dilutedwith 100 ml. of diethyl ether, the excess hydride decomposed by thecareful addition of 6.5 ml. of water in tetrahydrofuran, and the mixturefiltered. The filter was was slurried four times with hottetrahydrofuran, the mixture filtered, and the combined filtrates takento dryness in vacuo. The residue was suspended in benzene, and thesuspension was placed on a column of 300 g. of silica gel. The first twoand one half liters of eluate, eluted with benzene, and the next fourand one half liters, eluted with a mixture of 25 percent diethyl etherin benzene, were discarded. The next three liters of eluate, likewiseeluted with 25 percent diethyl ether in benzene, were collected andadded to the next liter and a half of eluate consisting of 50 percentdiethyl ether in benzene, the next six and a half liters consisting ofpercent diethyl ether in benzene, and the next liter and a halfconsisting of diethyl ether alone. The residues remaining afterevaporation to dryness of the above described fractions were combinedand recrystallized from a benzenelpetroleum ether mixture to give 1.54g. of l,2,3,4,6,7, l 2,1 Za-octahydro-2-phenylpyrazino[2 ',1 6,1]pyrido[3,4-b]indole, m.p. 231.6-233.6C. (corn).

Anal. Calcd. for c a m; C, 79.17; H, 6.98; N,

13.85. Found: C, 78.84; H, 7.15; N, 13.51.

EXAMPLE 40 EXAMPLE 41 1,2 ,3 ,4,6,7 ,1 2,1 2a-Octahydro-9,10-dimethoxy-2-(2,4- difluorophenyl)pyrazino[ ',1:6,l]pyrido[3,4-b]indole l4 2-(3-trif1uoromethylphenyl)pyrazino[2', 1':6,1]-pyrido[3,4-b]indole in tetrahydrofuran using the procedure describedabove in Example 39.

EXAMPLE 46 1,2,3 ,4,5 ,6,7 ,12,l2a-Octahydro-9-chloro-3-methyl-2-(2,4,6,-trimethylphenyl)pyrazino[2',l':6,1]pyrido[3,4- b]indole [1: R1is CH3; R2 is 2, 4, 6-(CH;,) R is 9- Cl] is prepared by lithium aluminumhydride reduction [1: R is H; R is 2,4-F R is 9,10-(CH O) is prepared bylithium aluminum hydride reduction of 1,2,3,4,6,7,12,12a-octahydro-1,4-dioxo-9,10-dimethoxy-2-(2,4-difluorophenyl)pyrazino[2 ',1 16,1 pyrido[3,4-b]indolein tetrahydrofuran using the procedure described above in Example 39.

EXAMPLE 42 1,2,3 ,4,6,'7,l 2,12a-Octhaydro-l0-ethoxy-2-(4-chlorophenyl)-pyrazino[2 ',1':6,1 ]pyrido[3,4-b]indole [1: R is H; R is4-C1; R is 10C H O] is prepared by lithium aluminum hydride reduction of1,2,3 ,4,6,7 ,12,12a-octahydro-1,4-dioxo-10-ethoxy-2-(4-chlorophenyl)pyrazino[2,1:6,l]pyrido[3 ,4-b]indole in tetrahydrofuranusing the procedure described above in Example 39.

EXAMPLE 43 1,2,3 ,4,6,7,12,12a-Octahydro-9-methyl-2-(3-methylmercaptophenyl)-pyrazino[2,l '1':6,1 ]pyrido[- b]indole [1: R, is H; R is 3-CH S; R is 9-CH is preparedby lithium aluminum hydride reduction of 1,2,3,4,6,7,l2,12a-octahydro-1,4-dioxo-9-methyl-2-(3-methylmercaptophenyl)pyrazino[2,1':6,1 ]pyrido[3,4-b]indole Intetrahydrofuran using the procedure described above in Example 39.

EXAMPLE 44 1,2,3 ,4,6,7,1 2,12a-Octahydro-9,1 l-dimethyl-2[4-(N.N-dimethylamino)phenyl]pyrazino[ 2',1 ':6,1] pyrido[3,4-b]indole [1:R is H; R is 4-(CH N; R is 9,1 l-(CH is prepared by lithium aluminumhydride 9,11-dimethyl-2-[4-(N,N-dimethylamino)phenyl]pyrazino-[2,1':6,1]pyrido[3 ,4-b]indole in tetrahydrofuran using theprocedure described above in Example EXAMPLE 45 1,2,3 ,4,6,7 ,12,12a-Octahydro-l0-benzyloxy-2-(3- triflouromethylphenyl)pyrazinoii2',1':6,l ]pyrido[3,4- b]indole [1: R is H; R 3-CF R is 10-C H CH O] isprepared by lithium aluminum hydride reduction of 1,2,3 ,4,6,7,l2,12a-octahydro-l ,4-dioxo-10-benzyloxyof1,2,3,4,6,7,12,12a-octahydro-1,4-dioxo-9-chloro-3-methyl-2-(2,4,6-trimethylphenyl)pyrazino[2', l':6,1]-pyrido[3,4-b]indole in tetrahydrofuran using the procedure describedabove in Example 39.

EXAMPLE 47 1,2,3 ,4,6,7,l 2,12a-Octahydro-10-bromo-2-(3,4-methylenedioxyphenyl)pyrazino[2',1:6,1]pyrido[3,4- b]indole [1: R is H;R is 3,4-OCH O;'R is 10-Br] is prepared by lithium aluminum hydridereduction of 1,2,3 ,4,6,7,12,12a-octahydro-1,4-dioxo-l0-bromo-2- (3,4-methylenedioxyphenyl)pyrazino[2 ,1 16,1 ]pyrido-[ 3,4-b]indole 25 intetrahydrofuran using the procedure described above in Example 39.

EXAMPLE 48 1,2,3 ,4,6,7,12,12a-Octahydro-10-fluoro-2-(3 ,4-

0 ethylenedioxyphenyi) pyraiino [2'1:6,1] pyrido [3, 4-b

' reduction of 1,2,3,4,6,7,12,12a-octahydro-l,4-dioxo- ]indole [1: R isH; R is 3,4-OCH CH O; R is 10-F] is prepared by lithium aluminum hydridereduction of l ,2,3,4,6,7,12,12a-octahydro-1,4-dioxo-10-fluoro-2- (3,4-ethylenedioxyphenyl )pyrazino 'ypyrazino 2,1':6,1bipyrido[3,4-b]indole in tetrahydrofuran using the proceduredescribed above in Example 39.

EXAMPLE 49 1,2,3 ,4,6,7, 1 2,12a-Octahydrol 0-iodo-2-( 3,4-diethoxyphenyl)-pyrazino[2,l:6,1]pyrido[3,4-b]indole [1: R is H; R is3,4-(C H O) R is 10-1] isprepared by lithium aluminum hydride reductionof 1,2,3,4,6,7,12,12aoctahydro-l ,4-dioxo- 1 O -iodo-2-( 3,4-diethoxyphenyl)pyrazino[2,l:6,1]pyrido[3,4-b]-indole intetrahydrofuran using the procedure described above in Example 39.

EXAMPLE 50 1,2,3 ,4,6,7 ,12,l2a-Octahydro-3-ethyl-9-hydroxy-2-(4-isopropylphenyl)pyrazino[2', 1 :6,1]pyrido[3 ,4-b]indole [1: R is C 11 Ris 4-(CH C1-1; R is 9-HO] is prepared by lithium aluminum hydridereduction of l,2,3,4,6,7,12,12a-octahydro-1,4-dioxo-3-ethyl-9-hydroxy-2-(4-isopropylphenyl)pyrazino-[2', 1:6,1]p yrido[3,4-b]indole intetrahydrofuran using the procedure described above in Example 39.

EXAMPLE 51 1,2,3 ,4,6,7,12,1Za-Octahydro-9-trifluoromethyl-2-(3-hydroxyphenyl)pyrazino[,1':6,1]pyrido[3,4-b]indole [1: R is H; R is3-HO; R is 9-CF is prepared by lithium aluminum hydride reduction of l,2,3,4,6,7,12,12a-octahydro-l,4-dioxo-9- trifluoromethyl-2-(3-hydroxyphenyl)pyrazino[2',l 6,1 ]pyrido[3,4-b]indole intetrahydrofuran using the procedure described above in Example 39.

EXAMPLE 52 1,2,3 ,4,6,7,l2,1Za-Octahydro-10-methylmercapto-2-phenylpyrazino-[2,1':6,l]pyrido[3,4-b]indole [1: R is H; R is H; R isl-CH S] is prepared by lithium aluminum hydride reduction of1,2,3,4,6,7,12,12a-octahydro-l ,4-dioxo-9 ,10-methylenedioxy-Z-phenylpyrazino[2',l ':6,1]pyrido[3 ,4-b]indole in tetrahydrofuran using theprocedure described above in Example 39.

EXAMPLE 53 EXAMPLE 54 1,2,3 ,4,6,7,l2,12a-Octahydro-9-amino-2-phenylpyrazino[2,1':6,1]-pyrido[3,4-b]indole[1; R is H; R is H; R is Q-NH is prepared by lithium aluminum hydridereduction of 1,2,3,4,6,7,12,12a-octahydro-1,4-dioxo-9-amino-2-phenylpyrazino{2',1':6,1]- pyrido[3,4-b]indole intetrahydrofuran using the procedure described above in Example 39.

EXAMPLE 55 1,2,3 ,4,6,7 ,12,1Za-Octahydro-l0-dimethylamino-2-phenylpyrazino-[2',1 '16,l]pyrid0[3,4-b]indo1e [1: R is H; R is H; R islO-(CH N] is prepared by lithium aluminum hydride reduction of1,2,3,4,6,7,l2,12a-0ctahydro-l,4-dioxo-10-dimethylamino-Z-phenylpyrazino[2',1 ':6,1 ]pyrido[3,4-b1indole in tetrahydrofuran using the procedure described above inExample 39.

EXAMPLE 56 1,2,3 ,4,6,7 ,12,12a-Octahydro-10-methyl-8-ch1oro-2-phenylpyrazino-[2,1:6,1]pyrido[3,4-b]indole [1: R is H; R is H; R is10-CH -8-Cl] is prepared by lithium aluminum hydride reduction ofl,2,3,4,6,7,12,12a-octahydro-l,4-dioxo-10-methyl-S-chloro-2-phenylpyrazino[2,1':6,11pyrido[3,4-blindole in tetrahydrofuran using the procedure described above inExample 39;

EXAMPLE S7 1,2,3,4,6,7,l2,12a-Octahydro-9,10-ethylenedioxy-Z-phenylpyrazino-[2',l16,1]pyrido[3,4-b]indo1e [1: R, is

H; R is H; R is 9,lO-OCH,CH 0] is prepared by lithium aluminum hydridereduction of 1,2,3,4,6,7,12,12aoctahydro- 1,4-dioxo-9,10-ethylenedioxy-Z-phenylpyrazino[2',1':6,1]pyrido{3,4-b]indole in tetrahydrofuran using the proceduredescribed above in Example 39.

I claim:

1. A compound having the formula wherein R, is hydrogen or lower-alkyl;and R R R5 and R are each a member of the group consisting of hydrogen,halogen, lower-alkyl, lower-alkoxy, lower-alkylmercapto, amino,di-lower-alkylamino, trifluoromethyl, or hydroxy in other than theeightposition, or R and R together or R and R together representmethylenedicxy or ethylenedioxy attached to adjacent carbon atoms, andwherein each of the loweralkyl containing moieties is stericallyaccommodatable alkyl containing from one to six carbon atoms.

2. A compound according to claim 1 wherein R R and R are each hydrogen.

3. 1,2,3 ,4,6,7,12,1Za-Octahydro-2-phenylpyrazino[ 2,,1:6,1]pyrido[3,4-b]ind0le according to claim 2 wherein R and R are eachhydrogen.

4. A compound having the formula wherein R is hydrogen or lower-alkyl;and R R R3 and R are each a member of the group consisting of hydrogen,halogen, lower-alkyl, lower-alkoxy, lower-alkylmercapto, amino,di-lower-alkylamino, trifluoromethyl, or hydroxy in other than theeightposition, or R and R together or R and R together representmethylenedioxy or ethylenedioxy attached to adjacent carbon atoms, andwherein each of the loweralkyl containing moieties is stericallyaccommodatable alkyl containing from one to six carbon atoms.

5. A compound according to claim 4 wherein R R and R are each hydrogen.

6. l,2,3,4,6,7, l 2,1 2a-Octahydro-l,4-dioxo-2-phenylpyrazino[2":6,1]pyrido[3,4-b]indole according to claim5 wherein R and R are each hydrogen.

I i i i l UNITED STATES PATENT AND TRADEMARK QFFICE CERTIFICATE OFCORRECTION PATENT NO. 3,717,638

DATED February 20, 1973 INVENTO I John W. Schulenberg It is certifiedthat error appears in the above-identified patent and that said LettersPatent are hereby corrected as shown below:

Column 1, lines 7 and 8, delete "ORGANIC COMPOUNDS AND THEIRPREPARATION.

' Column 2, line 23, change "formual" to read -formula-.

Column 2, line 61, "with in i" should read with formaldehyde in Column3, line 21, change "Therefor" to read Therefore- Column 4, line 3,delete "Example" Column 4, lines 16 and 17, change "energizes to readenergizers Signed and Scaled this Twenty-first D a y of June 1983 [SEAL]I A nest:

DONALD J. QUIGG Axles-ting Offibgr Acting Commissioner of Patents andTrademarks

1. A compound having the formula
 2. A compound according to claim 1wherein R1, R2 and R2'' are each hydrogen. 3.1,2,3,4,6,7,12,12a-Octahydro-2-phenylpyrazino( 2, '',1'':6,1)pyrido(3,4-b)indole according to claim 2 wherein R3 and R3'' are eachhydrogen.
 4. A compound having the formula
 5. A compound according toclaim 4 wherein R1, R2 and R2'' are each hydrogen.